tbuckley/cabot-search huggingface dataset:
A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes
Authors: Amer M. Zeidan, Uma Borate, Daniel A. Pollyea, Andrew M. Brunner, Fernando Roncolato, Jacqueline S. Garcia, Robin Filshie, Olatoyosi Odenike, Anne Marie Watson, Ravitharan Krishnadasan, Ashish Bajel, Kiran Naqvi, Jiuhong Zha, Wei‐Han Cheng, Ying Zhou, David Hoffman, Jason G. Harb, Jalaja Potluri, Guillermo Garcia‐Manero
Journal: American Journal of Hematology (2022)

Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m2 /day intravenously/subcutaneously. Responses were assessed per modified 2006 International Working Group (IWG) criteria. Forty-four patients (male 86%, median age 74 years) received venetoclax + azacitidine treatment. Median follow-up was 21.2 months. Hematological adverse events of Grade ≥ 3 included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common Grade ≥ 3 infection. Marrow responses were seen including complete remission (CR, n = 3, 7%) and marrow CR (mCR, n = 14, 32%); 36% (16/44) achieved transfusion independence (TI) for RBCs and/or platelets, and 43% (6/14) with mCR achieved hematological improvement (HI). The median time to CR/mCR was 1.2 months, and the median duration of response for CR + mCR was 8.6 months. Median OS was 12.6 months. Venetoclax + azacitidine shows activity in patients with R/R MDS following prior HMA therapy failure and provides clinically meaningful benefits, including HI and TI, and encouraging OS.
A Systematic Review of the Use of Commercial Wearable Activity Trackers for Monitoring Recovery in Individuals Undergoing Total Hip Replacement Surgery
Authors: Nasibeh Babaei, Negin Hannani, Nader Jafarnia Dabanloo, Shayan Bahadori
Journal: Cyborg and Bionic Systems (2022)

The innovation of wearable devices is advancing rapidly. Activity monitors can be used to improve the total hip replacement (THR) patients' recovery process and reduce costs. This systematic review assessed the body-worn accelerometers used in studies to enhance the rehabilitation process and monitor THR patients. Electronic databases such as Cochrane Database of Systematic Reviews library, CINAHL CompleteVR, Science Citation Index, and MedlineVR from January 2000 to January 2022 were searched. Due to inclusion criteria, fourteen eligible studies that utilised commercial wearable technology to monitor physical activity both before and after THR were identified. Their evidence quality was assessed with RoB 2.0 and ROBINS-I. This study demonstrates that wearable device technology might be feasible to predict, monitor, and detect physical activity following THR. They could be used as a motivational tool to increase patients' mobility and enhance the recovery process. Also, wearable activity monitors could provide a better insight into the individual's activity level in contrast to subjective self-reported questionnaires. However, they have some limitations, and further evidence is needed to establish this technology as the primary device in THR rehabilitation.
Influenza Incidence and Vaccine Effectiveness During the Southern Hemisphere Influenza Season — Chile, 2022
Authors: María Fernanda Olivares Barraza, Rodrigo A Fasce, Francisco Nogareda, Perrine Marcenac, Natalia Vergara Mallegas, Patricia Bustos Alister, Sergio Loayza, Anna N. Chard, Carmen Sofia Arriola, Paula Couto, Christian García Calavaro, Angel Rodriguez, David E. Wentworth, Cristóbal Cuadrado, Eduardo Azziz-Baumgartner
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

The COVID-19 pandemic has affected influenza virus transmission, with historically low activity, atypical timing, or altered duration of influenza seasons during 2020-22 (1,2). Community mitigation measures implemented since 2020, including physical distancing and face mask use, have, in part, been credited for low influenza detections globally during the pandemic, compared with those during prepandemic seasons (1). Reduced population exposure to natural influenza infections during 2020-21 and relaxed community mitigation measures after introduction of COVID-19 vaccines could increase the possibility of severe influenza epidemics. Partners in Chile and the United States assessed Southern Hemisphere influenza activity and estimated age-group-specific rates of influenza-attributable hospitalizations and vaccine effectiveness (VE) in Chile in 2022. Chile's most recent influenza season began in January 2022, which was earlier than during prepandemic seasons and was associated predominantly with influenza A(H3N2) virus, clade 3C.2a1b.2a.2. The cumulative incidence of influenza-attributable pneumonia and influenza (P&I) hospitalizations was 5.1 per 100,000 person-years during 2022, which was higher than that during 2020-21 but lower than incidence during the 2017-19 influenza seasons. Adjusted VE against influenza A(H3N2)-associated hospitalization was 49%. These findings indicate that influenza activity continues to be disrupted after emergence of SARS-CoV-2 in 2020. Northern Hemisphere countries might benefit from preparing for an atypical influenza season, which could include early influenza activity with potentially severe disease during the 2022-23 season, especially in the absence of prevention measures, including vaccination. Health authorities should encourage all eligible persons to seek influenza vaccination and take precautions to reduce transmission of influenza (e.g., avoiding close contact with persons who are ill).
<i>Notes From the Field:</i> Dispensing of Oral Antiviral Drugs for Treatment of COVID-19 by Zip Code–Level Social Vulnerability — United States, December 23, 2021–August 28, 2022
Authors: Meg Sullivan, Cria G. Perrine, Jimmy Kelleher, Om Kanwar, Sachiko Kuwabara, Kelly Bennett, Brendan R. Jackson, Pragna Patel, Meghan E. Pennini
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Equitable access to COVID-19 therapeutics is a critical aspect of the distribution program led by the U.S. Department of Health and Human Services (HHS).* Two oral antiviral products, nirmatrelvir/ritonavir (Paxlovid)† and molnupiravir (Lagevrio),§ received emergency use authorization (EUA) from the Food and Drug Administration (FDA) in December 2021, to reduce the risk for COVID-19-associated hospitalization and death for those patients with mild to moderate COVID-19 who are at higher risk for severe illness (1,2). HHS has been distributing these medications at no cost to recipients since their authorization. Data collected from provider sites during December 23, 2021-May 21, 2022, indicated substantial disparities in the population-adjusted dispensing rates in high social vulnerability (high-vulnerability) zip codes compared with those in medium- and low-vulnerability zip codes (3). Specifically, dispensing rates for the 4-week period during April 24-May 21, 2022, were 122 per 100,000 residents (19% of overall population-adjusted dispensing rates) in high-vulnerability zip codes compared with 247 (42%) in medium-vulnerability and 274 (39%) in low-vulnerability zip codes. This report provides an updated analysis of dispensing rates by zip code-level social vulnerability and highlights important intervention strategies.
<i>QuickStats:</i> Age-Adjusted Death Rates* for Stroke† Among Adults Aged ≥ 65 Years, by Region§ and Metropolitan Status¶ — National Vital Statistics System, United States, 2020
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

Age-adjusted rates are based on the 2000 U.S. Census Bureau standard population, using age groups 65-74, 75-84, and ≥85 years, with 95% CIs indicated by error bars.† Deaths for stroke were identified using International Classification of Diseases, Tenth Revision underlying cause of death codes I60-I69.§ Based on U.S. Census Bureau definition of four regions.https://www.census.gov/programs-surveys/popest/guidance-geographies/terms-and-definitions.html
Adolescent wellbeing and climate crisis: adolescents are responding, what about health professionals?
Authors: Alice McGushin, Giulia Gasparri, Viola Graef, Christophe Ngendahayo, Shashank Timilsina, Flavia Bustreo, Anthony Costello
Journal: BMJ (2022)

<b>Alice McGushin and colleagues</b> argue for recognition of the diverse ways in which climate change affects adolescent wellbeing and call for health professionals to work with them to respond to the crisis
Breaking down silos between health and education to improve adolescent wellbeing
Authors: Nicola J Gray, Nji Atanga Desmond, Danalaxshmi Shanen Ganapathee, Sally Beadle, Donald AP Bundy
Journal: BMJ (2022)

<b>Nicola Gray and colleagues</b> examine the mutual reinforcement of adolescent health and education, the challenges of intersectoral working, and the joint investment needed to secure wellbeing during adolescence, into adult life, and for the next generation
Adolescent connectedness: cornerstone for health and wellbeing
Authors: Robert W Blum, Joanna Lai, Michelle Martinez, Cassandra Jessee
Journal: BMJ (2022)

Connectedness is a cornerstone of healthy development• Government programmes focusing on reducing adolescent problem are mostly ineffective• Evidence suggests that success- ful programmes aim to strengthen connectedness with parents, peers, schools, and community• Future programmes should view young people as resources rather than problems
Four powerful reasons for increasing investment in adolescents and their wellbeing
Authors: David A Ross, Howard S Friedman, Darren Welch, Natasha S Kaoma, Rajesh Bhushan, Bruce Rasmussen
Journal: BMJ (2022)

Adolescents worldwide receive less public health investment per capita than other age groups. 1 2 This would be reasonable if adolescents' needs for investment were lower than those of other age groups, but this is not the case.The first two decades of a person's life are when they are learning the most and when values and behaviours are set for subsequent adult life. 3 Investing during adolescence will reap both short term and long term rewards for the adolescent themselves and for society.Failure to invest in crucial demographic groups is one reason for the prediction that few sustainable development goals (SDGs) will be met by 2030, according to the United Nations in its SDG report of July 2022. 4 Investment in adolescents and their wellbeing should be increased, therefore, for four powerful reasons.
H3.3K27M mutation is not a suitable target for immunotherapy in HLA-A2<sup>+</sup>patients with diffuse midline glioma
Authors: Lena Immisch, George Papafotiou, Oliver Popp, Philipp Mertins, Thomas Blankenstein, Gerald Willimsky
Journal: Journal for ImmunoTherapy of Cancer (2022)

Diffuse midline glioma is the leading cause of solid cancer-related deaths in children with very limited treatment options. A majority of the tumors carry a point mutation in the histone 3 variant (H3.3) creating a potential HLA-A*02:01 binding epitope (H3.3K27M 26-35 ). Here, we isolated an H3.3K27M-specific T cell receptor (TCR) from transgenic mice expressing a diverse human TCR repertoire. Despite a high functional avidity of H3.3K27M-specific T cells, we were not able to achieve recognition of cells naturally expressing the H3.3K27M mutation, even when overexpressed as a transgene. Similar results were obtained with T cells expressing the published TCR 1H5 against the same epitope. CRISPR/Cas9 editing was used to exclude interference by endogenous TCRs in donor T cells. Overall, our data provide strong evidence that the H3.3K27M mutation is not a suitable target for cancer immunotherapy, most likely due to insufficient epitope processing and/or amount to be recognized by HLA-A*02:01 restricted CD8 + T cells.
Comparison of PD-L1 tumor cell expression with 22C3, 28-8, and SP142 IHC assays across multiple tumor types
Authors: Jake G Maule, Lani K Clinton, Ryon P Graf, Jinpeng Xiao, Geoffrey R Oxnard, Jeffrey S Ross, Richard S P Huang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Multiple PD-L1 immunohistochemistry (IHC) assays, including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1 IHC assays, have been approved by the Food and Drug Administration as a companion diagnostic (CDx) for various antiprogrammed death-1 and antiprogrammed death ligand 1 (PD-L1) based cancer immunotherapies. Here we present 22C3, 28-8, and SP142 analysis of 418 tumor specimens encountered in routine clinical practice.All specimens were tested with 22C3, 28-8, and SP142 assays following the manufacturer's established staining protocols.The same PD-L1 status (defined as tumor cell expression (TC) scores with all three assays ≥1% or all &lt;1%) was observed in 60.0% (251/418) tumor specimens (45.9% (192/418) were triple negative and 14.1% (59/418) were triple positive). A total of 54.1% (226/418) tumor cases were positive with at least one IHC assay (94.2% (213/226), 77.0% (174/226), and 28.8% (65/226) of these were positive for 22C3, 28-8 and SP142, respectively). Among the 40.0% (167/418) tumor cases that showed a different PD-L1 status, 62.3% (104/167) were 22C3+/28-8+/SP142-, and 28.7% (48/167) were 22C3+/28-8-/SP142-. The same PD-L1 status with all three antibody clones was observed in 48.7% (97/199) of NSCLC cases, and among these, 54.6% (53/97) were triple negative and 45.4% (44/97) triple positive. A total of 73.4% (146/199) NSCLC cases were positive with at least one IHC assay (95.2% (n=139/146), 82.2% (n=120/146), and 32.2% (n=47/146) were positive for 22C3, 28-8, and SP142, respectively). Among the 51.3% (102/199) NSCLC cases that showed a different status among the three IHC assays, 67.6% (69/102) were 22C3+/28-8+/SP142-, and 23.5% (24/102) were 22C3+/28-8-/SP142-. A total of 81.1% (43/53) lung squamous cell carcinoma, 72.1% (88/122) of lung adenocarcinoma, 69.6% (16/23) of non-small cell lung cancer (NSCLC) not otherwise specified (NOS), and 50.0% (4/8) of small cell lung carcinoma cases were positive with at least one IHC assay.Our data suggest that 22C3 is the most sensitive PD-L1 IHC assay for tumor cell expression, followed by 28-8 and in turn by SP-142. These findings represent an additional factor for clinical teams to consider when deciding which PD-L1 IHC assay (and in turn which CDx-associated PD-L1 based immunotherapy) is most appropriate for each individual patient.
Comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with different covid-19 vaccines: international network cohort study from five European countries and the US
Authors: Xintong Li, Edward Burn, Talita Duarte-Salles, Can Yin, Christian Reich, Antonella Delmestri, Katia Verhamme, Peter Rijnbeek, Marc A Suchard, Kelly Li, Mees Mosseveld, Luis H John, Miguel-Angel Mayer, Juan-Manuel Ramirez-Anguita, Catherine Cohet, Victoria Strauss, Daniel Prieto-Alhambra
Journal: BMJ (2022)

Abstract Objective To quantify the comparative risk of thrombosis with thrombocytopenia syndrome or thromboembolic events associated with use of adenovirus based covid-19 vaccines versus mRNA based covid-19 vaccines. Design International network cohort study. Setting Routinely collected health data from contributing datasets in France, Germany, the Netherlands, Spain, the UK, and the US. Participants Adults (age ≥18 years) registered at any contributing database and who received at least one dose of a covid-19 vaccine (ChAdOx1-S (Oxford-AstraZeneca), BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), or Ad26.COV2.S (Janssen/Johnson &amp; Johnson)), from December 2020 to mid-2021. Main outcome measures Thrombosis with thrombocytopenia syndrome or venous or arterial thromboembolic events within the 28 days after covid-19 vaccination. Incidence rate ratios were estimated after propensity scores matching and were calibrated using negative control outcomes. Estimates specific to the database were pooled by use of random effects meta-analyses. Results Overall, 1 332 719 of 3 829 822 first dose ChAdOx1-S recipients were matched to 2 124 339 of 2 149 679 BNT162b2 recipients from Germany and the UK. Additionally, 762 517 of 772 678 people receiving Ad26.COV2.S were matched to 2 851 976 of 7 606 693 receiving BNT162b2 in Germany, Spain, and the US. All 628 164 Ad26.COV2.S recipients from the US were matched to 2 230 157 of 3 923 371 mRNA-1273 recipients. A total of 862 thrombocytopenia events were observed in the matched first dose ChAdOx1-S recipients from Germany and the UK, and 520 events after a first dose of BNT162b2. Comparing ChAdOx1-S with a first dose of BNT162b2 revealed an increased risk of thrombocytopenia (pooled calibrated incidence rate ratio 1.33 (95% confidence interval 1.18 to 1.50) and calibrated incidence rate difference of 1.18 (0.57 to 1.8) per 1000 person years). Additionally, a pooled calibrated incidence rate ratio of 2.26 (0.93 to 5.52) for venous thrombosis with thrombocytopenia syndrome was seen with Ad26.COV2.S compared with BNT162b2. Conclusions In this multinational study, a pooled 30% increased risk of thrombocytopenia after a first dose of the ChAdOx1-S vaccine was observed, as was a trend towards an increased risk of venous thrombosis with thrombocytopenia syndrome after Ad26.COV2.S compared with BNT162b2. Although rare, the observed risks after adenovirus based vaccines should be considered when planning further immunisation campaigns and future vaccine development.
Pembrolizumab combined with low-dose cyclophosphamide and intra-tumoral injection of the toll-like receptor 4 agonist G100 in patients with advanced pretreated soft tissue sarcoma: results from the PEMBROSARC basket study
Authors: Mariella Spalato-Ceruso, Fanny Bouteiller, Jean-Philippe Guegan, Maud Toulmonde, Alban Bessede, Michèle Kind, Sophie Cousin, Xavier Buy, Jean Palussiere, François Le Loarer, Berengere Dadone-Montaudie, Marina Pulido, Antoine Italiano
Journal: Journal of Hematology & Oncology (2022)

Abstract Soft tissue sarcomas (STS) are heterogeneous mesenchymal tumors with limited therapeutic options in the advanced setting. Immune checkpoint inhibitors have been shown to have significant clinical activity in inflamed STS which are characterized by the presence of tertiary lymphoid structures (TLS). New strategies are needed to sensitize TLS-negative STS to immunotherapy. Engagement of the toll-Like Receptor 4 (TLR4) signal pathway contributes to the development of a favorable tumor microenvironment in solid tumors. G100 is a highly potent toll-like receptor 4 (TLR4) agonist. We hypothesized that intra-tumoral G100 would induce a robust local and potentially systemic anti-tumor immune response in the microenvironment of TLS-negative sarcoma, leading to improved response to PD1 inhibition. Twenty metastatic STS patients who had a superficial injectable lesion were treated with 50 mg of cyclophosphamide (CP) orally twice daily (1 week on and 1 week off), 200 mg of pembrolizumab intravenously on day 8 of a planned 21-day cycle and G100 20 µg one weekly intra-tumoral injection for at least 6 weeks and for a maximum of 12 weeks (1st injection one week before CP administration, ie. Day -7). Biopsies and blood were collected pre and post treatment. Of the 17 patients assessable for efficacy analysis, 2 were progression-free at 6 months, and the 6-month non-progression rate was 11.8% (95% CI: 1.5–36.4), indicating that the first endpoint of the study was not reached. In 8 patients, there was an increase in T-cell infiltration into tumor after treatment. The ratio CD8/Fox-P3 + CD4 on treatment decreased in 11 cases out of 14 suggesting a predominant induction of Treg. Soluble PDL1 levels at baseline were also with adverse outcome. G100 appears to modulate the tumor microenvironment with significant infiltration of T cells. However, clinical activity in combination with PD1 inhibition was limited and no clear correlation was observed between tumor shrinkage and increased inflammation. TLR4 stimulation might have both antitumor and pro-tumor consequences. Trial registration : This study was registered with ClinicalTrial.gov, number NCT02406781.
Building transformational intergenerational partnerships for adolescent wellbeing
Journal: BMJ (2022)

Building transformational intergenerational partnerships for adolescent wellbeingIn this open letter, youth representatives and political leaders argue that adolescents should be engaged as equal stakeholders in decision making and agenda setting in all efforts to further their wellbeing globally Adolescents want a future in which they are supported towards a healthy transition into adulthood, with a whole society approach centred on their lived reality.This requires policy making and programming to go beyond meeting essential needs and to remove the multiple barriers (social, structural, legal) that limit achievement of full potential and holistic wellbeing.It is also important to focus on adolescents' right to self-fulfilment, equitable opportunity, agency and autonomy, and positive development.As young leaders and government allies, we call on policy makers, youth centred agencies, and key stakeholders to deliver more meaningfully for adolescents-recognising diversity and the needs of those most at risk of being left behind.Engaging adolescents as equal stakeholders in decision making and agenda setting is important, recognising them as experts in defining their own wellbeing.Frequently, wellbeing interventions are developed from the perspective of adults, without meaningful participation of adolescents in design, implementation, or evaluation, 1 leading to services that are not accessible or truly responsive to their needs. 2Adolescents are frequently regarded as respondents, audiences, or beneficiaries, or provide tokenistic validation of supposedly youth focused policies and programme efforts, which unsurprisingly then lack effectiveness and impact.